Adolescent substance use is common and associated with both significant negative individual consequences and substantial costs to society. The proposed study will capitalize on a cost-effective opportunity to identify neurobiological mechanisms underlying risks for, and consequences of, adolescent substance use. Tests will be conducted in adolescents with high (n= 68) and low (n = 34) familial risk for substance use disorders, selected from a larger ongoing longitudinal study that is testing causal relationships between the development of impulse control and substance use. In this new application, we seek to identify relationships between maturation of frontostriatal circuitry, impulse control development, and progression of substance use involvement across adolescence. We propose to measure frontostriatal circuitry in 11- to 14- year-old adolescents at risk for substance use disorders and to repeat assessments annually for a 5-year period. We will compare circuitry between adolescents at high or low risk for substance use disorders (based on family history) before regular drug use begins (Aim 1); determine how individual differences in early adolescent frontostriatal circuitry development, before regular drug use, predict onset and severity of substance use (Aim 2); and examine how trajectories of frontostriatal circuitry development are affected by both familial risk and adolescent substance use (Aim 3). This application posits that a) impulsive reward- focused behaviors emerging during adolescence are driven, at least in part, by inadequate regulation of the striatum due to delayed maturation of the prefrontal cortex, and b) that adolescents are uniquely vulnerable to substance use disorders and resultant cognitive impairments. This framework allows for testable hypotheses to examine neurobiological mechanisms underlying relationships observed between impulse control and substance use disorders across adolescent development. This is an opportunity to study the etiology of adolescent substance use by examining neurobiological mechanisms underlying risk for substance use disorders, impulse control development, and effects of substance use on adolescent brain development. Our study has the unique advantage of recruiting from an established and well-characterized cohort that is being followed longitudinally. A strong interdisciplinary research team is in place which combines unique expertise in substance abuse research, advanced imaging methodology, adolescent behavioral assessment, and statistical modeling. This proposal integrates distinct bodies of research on brain development, adolescent behavior, and substance abuse to advance understanding of risks and consequences of adolescent substance use. PUBLIC HEALTH RELEVANCE: This proposal integrates distinct bodies of research on brain development, adolescent behavior, and substance abuse to advance understanding of risks and consequences of adolescent substance use. This work has important implications for advancing knowledge, and ultimately may contribute to more effective treatment and prevention strategies for adolescent substance use disorders.